Adenosine mediates a wide variety of effects as a result of its activation of specific membrane-bound receptors called P1-purinoceptors. The three subclasses of P1-purinoceptors are A1, A2 and A3, with A2 further subdivided into A2A and A2B. All adenosine receptors are coupled to the enzyme adenylate cyclase; activation of the A1 and A3 adenosine receptors inhibit the adenylate cyclase, whereas activated A2A and A2B receptors stimulate it. The adenosine A2A receptor can be found throughout the whole body, and A2A receptor agonists might be used to inhibit platelet aggregation in thrombosis, in the diagnosis of diseases in coronary arteries, in ischemia and reperfusion.1 Furthermore, activation of adenosine A2A receptors has been shown to alter the binding characteristics of other receptors. Stimulation of adenosine A2A receptors in rat striatal membranes reduces the affinity of agonist binding to dopamine D2 receptors.2,3 This raises the possibility of using adenosine A2A receptor agonists as a novel therapeutic approach in the treatment of psychosis. However, these desired actions of agonists for the adenosine A2A receptor may be accompanied with serious side effects such as cardiovascular actions, since the receptor is ubiquitously distributed. The design of partial agonists for the adenosine receptors has already been shown to be a useful tool to achieve selectivity of action in vivo by exploitation of the differences in receptor-effector coupling in various tissues.4-7 Hence, partial agonists for the adenosine A2A receptor might then be developed as antipsychotic agents also devoid of undesired cardiovascular actions.
Selectivity for the adenosine A2A receptor can be obtained by the introduction of a C2-substituent, such as a 1-hexynyl or a 1-hexenyl group that have been shown to induce high affinity for the adenosine A2A receptor compared to A1.8-10 Partial agonism for adenosine receptors in general has been achieved by the introduction of alkylthio-substituents at the 5′-position.5,11 However, partial agonism for the adenosine A1 receptor has also successfully been accomplished by introducing alkylamino substituents at the C8-position of adenosine.12 8-Alkylamino substituted CPA derivatives have proven to be adenosine A1 receptor partial agonists in vivo when assessed for cardiovascular activity, although with modest affinities.6,13,14 